4alpha, 8, 14-trimethyl-18-nor-delta12-5alpha, 8alpha, 9beta, 14beta-androstene-3alpha-ol-17-one and derivatives thereof



ates Patent ()fi 3,376,324 Patented Apr. 2, 1968 ice 4a .8,14 TRIMETHYL 18 NOR A 5a,8a,9,B,14/3- ANDROTENE 30c L 17 GNE AND DERIV- ATIVES THEREOF Patrick A. Diassi, Westfield, N.J., assignor to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware N0 Drawing. Continuation-impart of application Ser. No. 406,877, Oct. 27, 1964. This application June 15, 1966, Ser. No. 557,608

9 Claims. (Cl. 260-3973) ABSTRACT OF THE DISCLOSURE The disclosure herein relates to fusidic acid derivatives. The compounds claimed herein are useful in the treatment in such conditions as bursitis.

This application is a continuation-in-part application of US. application, Ser. No. 406,877, filed Oct. 27, 1964, now abandoned.

'T his invention relates to and has as its object the provision of new physiologically active steroids, methods for their production and novel intermediates useful in the preparation thereof.

More particularly, this invention relates to the production of steroids of the general formulae wherein R is hydrogen; R is selected from the group consisting of hydroxy and acyloxy; and taken together R and R is oxo (0:).

The preferred acyloxy radicals are those of hydrocarbon earboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric and tert-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and B-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkenecarboxylic acids.

The final products of this invention are physiologically active and may be employed in cornbination with such solvents a dimethyl sulfoxide or tetrahydrothiophene-l,1- dioxide in the treatment of such conditions as bursitis and rheumatoid arthritis, the concentration and/ or dosage being adjusted for the relative potency of the compound employed.

The final products of this invention may be prepared by the process of this invention which entails a number of steps beginning with methyl fusidate as starting material. The steps of the process of this invention may be represented by the following equations wherein R, R, R" and R may represent hydrogen, alkyl, acyl or 0x0 (0:):

In the first step of this invention, methyl fusidate is .acylated as by treatment with an acid anhydride, for

9 example, acetic anhydride, to yield the 3,11-diacyloxy derivative thereof, a new compound of this invention.

[In this application and in the appended claims, whenever in the formulae set forth herein line is employed in the linkage of atoms, it is meant to denote that the connected atom may be either in the alpha or beta position, for example, in Compounds E the 183 epimer may be treated with an alkali metal base, for example, potassium hydroxide to yield the 180: derivative] The 3,1l-diacyloxy derivative of methyl fusidate is then first ozonized and then reduced to yield a mixture of Compounds B, C and D, which are also new compounds of this invention.

Compounds C and D may then be hydrogenated to yield the saturated Compound E. Hydrolysis of Compounds C and D gives Compounds F and D (R=H), respectively.

Compounds F and D (R -H) may then be oxidized as by treatment with an oxidizing agent, for example, chronium trioxide to yield the 3-keto derivatives which are new final products of this invention.

Compounds F may then be hydrogenated as by treatment with hydrogen in the presence of a palladium catalyst to yield the saturated 3-keto derivatives (Compounds E) which are also new final products of this invention.

Alternatively, the compounds of this invention may be prepared from the intermediate having the formula R CH3 The invention may be illustrated by the following examples:

Example 1.Methyl fusidate 3,11-diacetate Forty grams of methyl fusidate are added to a solution of 40 g. of p-toluenesulfonic acid and 80 ml. of acetic anhydride in 160 ml. of acetic acid and the mixture left at room temperature for twenty minutes. The solution is then carefully diluted with ice while stirring, then diluted with water and extracted with chloroform. The chloroform is then washed several times with water and evaporated to dryness in vacuo, to give 46 g. of crude methyl fusidate 3,11-diacetate.

Similarly, if propionic anhydride or butyryl anhydride are substituted for acetic anhydride, the dipropionate and dibutyrate are obtained, respectively.

Example 2.4a,8,l4-trimethyl 18 n0rA -5a,8u,l4l3- androstene-3e-ol-17-one 3-acetate, 4a,8,14-trimethyl- 4 18 nor A -5oc,8ot,9[3,l4[3 androstadiene-3e-ol-17- one B-acetate and 4u,8,14-trimethyl-l8-nor-A -5u,8e, 913,135,1419-androstene 3a,11a diol 17 one 3,11- diacetate A solution of 6 g. of methyl fusidate 3,1l-diacetate in a mixture of 122 m1. of methylene chloride and 1.22 ml. of pyridine is cooled in an acetone-Dry Ice bath and 443 liters of ozonized oxygen (1.1 mmoles 0 per liter) are slowly passed through. Twelve milliliters of acetic acid and 6 g. of zinc dust are then added and the mixture stirred vigorously at room temperature for ninety minutes. It is then filtered and washed with chloroform. The combined filtrate and washings are then extracted successively with water, 5% sodium bicarbonate and water, dried over anhydrous magnesium sulfate and evaporated to dryness, in vacuo. The residue is then redissolved in 500 ml. of acetic acid, 11 g. of zinc dust is added and the mixture refluxed for four hours. It is then filtered, diluted with water and extracted with chloroform. The chloroform is washed well with water and then evaporated to dryness, in vacuo. The residue is dissolved in chloroformzhexane (1:1, v.:v.) and plate chromatographed using Weolm neutral alumina(Activity V) as adsorbent and chloroform-hexane (1:1, v.:v.) as developing solvent.

The band detectable by UV. at Rf 0.3-0.7 eluted by ehtyl acetate evaporated to dryness and crystallized from acetone-hexane to give 663 mg. of 4a,8,l4-trimethyl-l8- nor-A -5u,8e,9;3,14fi-androstene 3a ol-17-one 3-acetate having a melting point about 138-140";

[a] 260 (chlf.), A3}; 245 mp. (e, 9500), 5.88, 610p.

1' 33.37 (m., 12-11), 5.09 (m., Sfi-H), 7.93 (s., 3-acetate), 8.83 (s., methyl), 8.95 (s., methyl), 8.98 (s., methyl), 9.15 (d., 1:6,4-rnethyl).

Analysis.-Calcd for C H O (358.50): C, 77.05; H, 9.56. Found: C, 77.39; H, 9.29.

The band detectable by UV. which had an Rf:0.2 is eluted with ethyl acetate and the residue after removal of the solvent on crystallization from acetone-hexane gives 20 mg. of 401,8,14-trimethyl-l8-nor-A -5a,8u,9;9,13B, 14fl-androstene-3a,11a-diol-l7-one 3,11-diacetate having a melting point of about 215-217 [ah 82 (chlf.), A512,, 226 my (6, 8400), A222" 5.80 5.90, 6.30;:

material obtained from this band from acetone-hexane 14p-androstadiene-3 a-ol-17-one 3-acetate having a melting point about 173-175",

[0411) 47 (chlf.), A513, 248 m (e, 9300), A221? 5.81,

1- 2.51 (d., 1:6, 15-H), 3.50 (m., 12-11), 3.81 (d., 1:6,

16-H), 5.08 (m., 3fl-H), 8.80 (s., methyl), 8.93 (s.,

methyl), 9.14 (d., 1:5, 4-methyl), 9.19 (s., methyl).

Analysis.Calcd for C H O (356.47): C, 77.49; H,

0.95. Found: C, 77.42; H, 9.13.

androstane-3a,ol-l7-one 3-acetate To a solution of 400 mg. of 411,8,l4-trimethyl-18-nor- A -5a,8a,9fl,l4,3-androstene-3a-ol-17-one 3-acetate. in 56 ml. of absolute ethanol 400 mg. of 5% palladium on calcium carbonate are added and the stirred mixture hydrogenated at room temperature for sixteen hours. The mixture is filtered and evaporated to dryness in vacuo. Crystallization of the residue from acetone-hexane gives 33] mg. of 4a,8,14-trimethyl-18-nor-5a,8 x,9;8,13fi,14;3-andro. stane-3a-ol-17-one having a melting point about 143 145 [01], +l8 (chlf.), E13? 5.78

1- 5.05 (m., 35-11) 7.96 (s., 3-acetate), 8.71 (s., methyl), 9.06 (s., methyl) 9.10 (s., methyl) and 9.17 (d., 1:6, 4- methyl).

Analysis.-Calcd for C H O (360.52): C, 76.62; H, 10.07. Found: C, 76.63; H, 9.82.

Example 4.4a,8,14,-trimethyl-18-nor-5a,8u,9 8,13,9,14/3- androstane-3u-ol-17-one 3-acetate Following the procedure of Example 3, but substituting 401,8,14 trimethyl-18-nor-A 5a,8a,9 3,14,8-androstadiene-3a-ol-17-one 3-acetate for the 4u,8,14-trimethyl-18- nor 12,5u,8a,9,3,14B-androstene-3a-ol-17-one Ev-acetate, there is obtained the desired product.

Example 5 .4a,8,14-trimethyl-18-nor-A -5 ct,80c,9f3,14flandrostadiene-3 u-ol-17-one A solution of 107 mg. of 4a,8,14-trimethyl-18-nor l2,15-5a,8a,9,3,14,9-androstadiene-3a-ol-17-one 3-acetate in m1. of 1 N potassium hydroxide in 95% ethanol is blanketed with helium and left at room temperature for sixteen hours. The solution is then neutralized with 2 N hydrochloric acid diluted with water and extracted with chloroform. The chloroform is washed with water and evaporated to dryness, in vacuo. Crystallization of the residue from acetone-hexane gives 75 mg. of 4oz,8,l4- trimethyl 18 nor 12,15,5a,8c=,9fi,14fi-androstadiene- 3a-0l-17-01'16 having a melting point about 184-186,

3 23 (chlf), 3, 11,, 249 my (6, 7500 A222 2.00, 5.95, 6.08, 6.30,.

'r 2.56 (d., 1:6, -H), 3.54 (m., 12-H), 3.92 (d., 1:6, 16-1-1), 6.28 (m., 35-1-1), 8.83 (s., methyl), 8.96 (s., methyl), 9.06 (d., 1:6, 4-methyl), 9.22 (s., methyl).

Example 6.4a,8, 14-trimethyl-18-nor-A -5 (1,8 11,9 3,145- androstene-3a-ol-17-one Following the procedure of Example 5, but substituting 4a,8,14 trimethyl 18-nor-A -5u,8a,9,8,14 8-androstene- 3a-ol-l7-one 3-acetate for 4a,8,14-trimethyl-18-nor-A 511,813,913,14fl-androstadiene-3a-ol-17-one 3-acetate, there is obtained 40:,8,14-trimethyl-18-nor-A -5a,8a,9fi,14fl-androstene-3u-ol-17-one.

Example 7.4a,8,14-trimethyl-18nor-A -5a,8a,9[3,14 3- androstadiene-3 ,17-dione To a solution of 50 mg. of 40 8,14-trimethy1-l8-nor- A -5a,8a,9;9,14fl-androstadiene-3a-ol-17-one in 2 ml. of reagent grade acetone a solution containing mg-./ml. of chromic anhydride and 32 mg./ml. of sulfuric acid in acetone-water (9: 1, v.:v.) is added dropwise until the oxidizing agent is no longer decolorized. After five minutes the excess oxidizing agent is decomposed with methanol and on careful dilution with water crystals separate. These are filtered, washed with water and dried. Recrystallization from acetone-hexane gives 41 mg. of 4a,8,14 tl'imethyl 18 nor-A -5a,8a,9;8,14 5-androstadiene-3,17- dione having melting point about 174-176",

A3}; 247 my (e, 9200), [001 +15 (chlf.), A231? 5.90 6.02, 6.30;;

7' 2.54 (d., 1:6, 15-H), 3.54 (m., 12-11), 3.88 (d., 1:6, 16-11), 8.72 (s., methyl), 8.77 (s., methyl), 8.97 (d., 1:6, 4-methyl), 9.23 (s., methyl).

Analysis.-Calcd for C H O (312.44): C, 80.73; H, 9.03. Found: C, 80.78; H, 9.00.

6 Example 8.4a,8, 14-trimethyl-18-nor-A -5a,8 z,9fi, 14 8- androstene-3,17-dione Following the procedures of Example 7, but substituting 4a,8,14-trimethyl-18-norA -5a, 8 u,9;3,14fi-androstadiene-3a-ol-17-one for the 411,8,14-trimethyl-18-nor-A 5a,8a,9fi,14 3-androstadiene-3,17-dione having a melting point about 153-155",

[ lu -219 Mia. 6.04

246 my (6, 8300), Am? 5.88,

-r 6.27 (m., 3-H), 8.72 (s., methyl), 9.08 (s., methyl), 9.10 (d., 1:6, 4-rnethyl), 9.11 (s., methyl).

AnaZysis.-Calc'd for C H (318.48): C, 79.199; H, 10.76. Found: C, 79.18; H, 10.81.

Example 10.4oc,8, 14-trimethyl-18-nor-5ot,8a,9;3,1301,145- androstane-3a-ol-17-one A solution of 100 mg. of 411,8,14-trimethyl-18-nor-5a- 8a,9 9,13fi,14,8-androstane-3a-ol-17-one 3-acetate in 10 ml. of 1 N potassium hydroxide in ethanol is kept at room temperature under helium for sixteen hours. It is then neutralized with 10% acetic acid diluted with water and extracted with chloroform. The chloroform extracts are washed with water and evaporated to dryness, in vacuo.

Plate chromatography of the residue using Woelm neutral alumina (Activity V) as adsorbent, and chloroform as the developing solvent gave two bands detectable by iodine vapor at Rf 0.6 and 0.4, respectively. Elution of the less polar band with ethyl acetate and crystallization of the residue from acetone-hexane after removal of the solvent gives 11 mg. of 41,8,14-trimethyl-18-nor- 5a,8a,9;9,13a,14fi-androstane-3a-ol-17-one having a melting point about 215-217,

'7 6.23 (m., 3-H), 8.76 (s., methyl), 9.07 (d., 1:6, 4- methyl), 9.11 (s., methyl), 9.13 (s., methyl).

Analysis-Calcd for C H O (318.48): C, 79.19; H, 10.76. Found: C, 79.16; H, 10.63.

Example 11.-4a,8,14-trimethyl-l8-nor-5a,8a,9;9,1319,1413- androstane-3,17-dione Oxidation of 404,8,14-trimethyl-18-nor-5zx,8a,9fi,135, 14fi-androstane-3u-ol-17-one following the procedure as described in Example 7 gives 406,8,14-trimethyl-18-nor- 5u,8a,9;5,13fl,14,8-androstane-3,17-dione having a melting point about 182-184",

1- 8.68 (s., methyl), 8.93 (s., methyl), 8.98 (d., 1:6, 4- methyl), 9.13 (s., methyl).

Analysis.Calcd for C H O (316.47): C, 79.70; H, 10.19. Found: C, 79.79; H, 19.14. Example 12.40z,8, 14-trimethyl-1 8-nor-5a,8a,95, 1313,1413- androstane-3,20-dione Following the procedure of Example 3, but substituting 4ot,8,14 trimethyl 18 nor-12,5m,8a,9 3,14fi-androstene- 2,17-di0ne for the 4a,8,14-trimethyl-18-nor-12,5a,8a,9fi,

7 l4B-androstene-3a-ol-l7-one 3-acetate, there is obtained the desired product.

Example 13.-4a,8,14-trimethyl-18-nor- -5u,8m,9p3,14;8 androstadiene-3 ot-ol-17-one A solution of 40:,8,l4-tI'imethy1-18nOI- -5oc,8a,9fl, l4fl-androstadiene-3a-ol-17-one 3-acetate in 5% methanolic KOH and water is refluxed under nitrogen for seven and one-half hours. The solution is then acidified with glacial acetic acid and the resulting solution concentrated in vacuo. Water is added and after cooling the resulting crystals are removed by filtration, to yield the desired product.

Example 14.-3 et,1 1oz, l6B-triacetoxy-4a,8,14-trimethyl- 18-nor-5a, 8 11,95,131 02, 14B-androstanl7 -0ne A solution of 6 g. of methyl fusidate 3,11-diacetate in a mixture of 122 ml. of methylene chloride and 1.22 ml. of pyridine is cooled in an acetone-Dry Ice bath and 443 liters of ozonized oxygen (1.1 rnmolcs liter) and slowly passed through. Twelve milliliters of acetic acid and 6 g. of zinc dust are then added and the mixture stirred vigorously at room temperature for ninety minutes. It is then filtered and washed with chloroform. The combined filtrate and washings are then extracted successively with water, sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated, in vacuo. Plate chromatography of the residue on neutral alumina (Activity V) gave one elution with chloroform 3a,11a,16fl-triacetoxy- 401,8,14 trimethyl 18-nor-5m,8a,9fl,13a,l4;3-androstane- 17-one having a melting point about 149-151,

(m., H-C--OAc), 5.10 (m., HC--OAc), 7.86 (s., OAc,) 7.92 (5., OAc), 7.98 (s., OAc), 8.50 (s., CH 9.01 (s., CH 9.03 (s., CH 9.15 d., 1:6, 4tZCH3), [a] -104 (chloroform).

Example 15.4oz,8,l4 trimethyl 18 nor-5a,8a,8,8,14/3- androst 12 ene 30: 01 l7-one-3-acetate; 4a,8,14- trimethyl l8 nor-5a,8oz,9,8,14fl-androsta-12,15,diene- 3a ol 17 one-3-acetate and 4a,8,14-trimethyl-18- nor 5a,8a,9fl,13}9,14fi androst-l5-cne-3a,1la-diol-17- one-3,12-diacetate By refluxing 30:,11a,16,9-triacetoxy-4a,8,14-trimethyl- 18 nor-5a,8a,9p,13a,l4fl-androstan-17-one with zinc dust in acetic acid as described in Example 2, the above compounds are obtained.

Example 16.-3 0:,1la-diacetoxy-4a,8,14-trimethyl-18-nor- 5a,8a,95,14ot-androstan-17-one A solution of mg. of 3a,11a-diacetoxyta,8,14-trimethyl 18 -nor-5018119 8,14fl-androst-15-ene-17-one in 5 ml. of absolute ethanol is hydrogenated at room temperature and atmospheric pressure using 25 mg. of 5% palladiurn or calcium carbonate as catalyst. The mixture is then filtered, evaporated and the residue crystallized from acetone-hexane to give 23 mg. of 3a,11a-di8.C6tOXy-4a,8, 14-trimethyl-18-nor-5u8a,9,8,14fi-androstan-17-one having a melting point about 186-188", [01.] --114, [M 1400 1350 1330 1305 +80, [d i0 (in methanol).

Analysis.Calcd for C H O (418.55): C, 71.74; H, 9.15. Found: C, 71.87; H, 9.00.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of steroids of the formulae and N 1; i; C H: C H:

wherein R is hydrogen; R" is selected from the group consisting of hydroxy and acyloxy; wherein the acyl radical is of a hydrocarbon car-boxylic acid of less than twelve carbon atoms; and together R and R" is 0x0 (0:).

2. A- compound of the formula wherein R and R" are as defined in claim 1.

3. A compound having the formula R20 H R! RQBA: on

t F" I 67H: H

mo" R V (3H1 7. A compound in accordance with claim 1 having 8. A compound in accordance with claim 1 :having the name 4a,8,l4trimethyl-18-nor-5a,8a,9fl,135,145-2111- drostane-3,17-dione.

9. A compound in accordance with claim 3 having the name 3a,11a,165-triacetoxy-4a,8,14-trimethyl-18-nor- 5a,8a:,9fl-130t, 14 3-androstan-17-one.

References Cited UNITED STATES PATENTS 9/1966 Krakower 260397.45

OTHER REFERENCES Godtfredsen et al.: Tetrahedron (1962), vol. 18, p. 1037.

ELBERT L. ROBERTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 ,376 ,324 April 2 1968 Patrick A. Diassi It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, last formula at the bottom of the column should be labeled G Column 3, line 38, heerinabove" should read hereinabove lines 46 to 56, the upper right-hand portion of the formula should appear as shown below:

line 74, "5a,8a,148" should read 5d,8d,96,146 Column 4, line 26, "ehtyl" should read ethyl line 33, "33.37" should read 3.37 line 69, "0.95" should read 9.05 Column 6, line 28, "79.199" should read 79.19 line 69, "19.14" should read 10.14 Column 7, lines 3 and 5, "nor each occurrence, should read nor-12,15, line 19 "0 liter" should read 0 per liter line 28 "one" should read on line 39 "8 B" should read 9B line 53, "ene" should read en Signed and sealed this 2nd day of December 1969.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents 

